Benzofurane derivatives

ABSTRACT

Benzofurane derivatives of formula (I), wherein R and R′ have the meanings given in claim no. ( 1 ), and salts thereof are suitable for use as intermediate products in the synthesis of medicaments.

The invention relates to benzofuran derivatives of the formula I.

in which

R is 1-piperazinyl, 4-R¹-piperazinyl or L,

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazinyl-1-ylcarbonyl,N,N-di(tert-butyloxy-carbonyl)aminocarbonyl, —CH═C(R⁵R⁶),benzofuran-2-yl-C≡C—, —C(Hal)₃, —CO—C (Hal)₃,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

L is Cl, Br, I or a free or reactive functionally modified OH group,

R¹, R⁴ in each case independently of one another are H, benzyl oranother amino protective group,

R², R³ in each independently of one another are H or alkyl having 1-6 Catoms,

R⁵, R⁶ in each case independently of one another are alkyl having 1-6 Catoms,

Hal is F, Cl, Br or I,

and their salts.

Similar compounds are disclosed in DE 43 33 254 and DE 195 14 567.

The invention was based on the object of finding novel compounds whichcan be used, in particular, as intermediates in the synthesis ofmedicaments, but can also be used directly for the production ofmedicaments.

It has been found that the compounds of the formula I and their saltsare important intermediates for the production of medicaments and at thesame time have pharmacological properties. Thus, they show, for example,effects on the central nervous system.

The invention relates to the benzofuran derivatives of the formula I andtheir salts.

Above and below, the radicals R¹, R², R³, R⁴, R⁵, R⁶, R, R′, L, Q and Q′have the meanings indicated in the formulae I to V, if not expresslystated otherwise. In the above formulae, A has 1 to 4, preferably 1, 2or 3, C atoms. A is preferably methyl or ethyl, furthermore propyl orisopropyl, and additionally also butyl, isobutyl, sec-butyl ortert-butyl. The radical Ph is phenyl.

In the compounds of the formula [sic] I, II, V, VI and VII, L, Q and Q′are preferably Cl, Br, I or a reactive modified OH group such as, forexample, an activated ester, an imidazolide or alkylsulfonyloxy having1-6 C atoms (preferably methylsulfonyloxy) or arysulfonyloxy having 6-10C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The expression “amino protective group” is generally known and relatesto groups which are suitable for protecting (for blocking) an aminogroup from chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out at other positions in themolecule. Typical of such groups are, in particular, unsubstituted acyl,aryl, aralkoxymethyl or aralkyl groups. As the amino protective groupsare removed after the desired reaction (or reaction sequence), theirnature and size is otherwise uncritical; preferred groups, however, arethose having 1-20, in particular 1-8 C atoms. The expression “acylgroup” is to be interpreted in the widest sense in connection with thepresent process and the present compounds. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids and also, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acylgroups of this type are alkanoyl such as acetyl, propionyl, butyryl;aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl;aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such asCBZ (carbobenzoxycarbonyl, also called “Z”), 4-methoxybenzyloxycarbonyl,FMOC (9-fluorenylmethoxycarbonyl); arylsulfonyl such as Mtr(4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protectivegroups are BOC and Mtr, and additionally CBZ or FMOC.

The compounds of the formula I can have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula I includesall these forms.

The invention further relates to a process for the preparation ofbenzofuran derivatives of the formula I according to claim 1 and oftheir salts, characterized in that

a) for the preparation of compounds of the formula I in which

R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl and

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-yl carbonyl,1,4-dihydrobenzo[d] [1,2]-oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

a compound of the formula II

 in which

R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl and

Q is Cl, Br, I or a free or reactive functionally modified OH group,

and R¹ has the meaning indicated in claim 1

is reacted with a compound of the formula III

R′—H  III

 in which

R′ is 2-R²-5-R³-pyrrol-1-yl, 4-R⁴-piperazin-1-yl,1,4-dihydrobenzo[d][1,2]oxazin-3-yl or3,4-dihydrobenzo-1H-phthalazin-2-yl,

and R², R³ and R⁴ have the meanings indicated in claim 1, or

b) for the preparation of compounds of the formula I in which

R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl and

R′ is —CH═C(R⁵R⁶), benzofuran-2-yl-C≡C—, —C(Hal)₃ or —CO—C(Hal)₃,

and R¹, R⁵ and R⁶ have the meanings indicated in claim 1,

i) a compound of the formula IV

 in which

R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, is reacted with acompound of the formula V

Q′—CH₂—CO—R′  V

 in which R′ is —CH═C(R⁵R⁶), benzofuran-2-yl-C-≡C—, —C(Hal)₃ or—CO—C(Hal)₃,

and Q′ is Cl, Br, I or a free or reactive functionally modified OHgroup,

and R⁵ and R⁶ have the meanings indicated in claim 1, or

ii) a compound of the formula Va

 in which R and R′ have the meanings indicated under i) is cyclized, or

c) a compound of the formula I,

 in which R is a 1-piperazinyl radical, is converted by introduction ofan amino protective group into another compound of the formula I inwhich R is the 4-R¹-piperazinyl radical,

in which R¹ is an amino protective group, or

d) a compound of the formula I,

 in which R is a 4-R¹-piperazinyl group, in which R¹ is benzyl oranother amino protective group, is converted by removal of the benzyl oramino protective group into a compound of the formula I in which R¹ is1-piperazinyl, or

e) in a compound of the formula I a radical R is converted into anotherradical R

by, for example,

i) replacing a Br atom by OH,

ii) esterifying an OH group or

iii) replacing a Br atom by a 4-R¹-piperazinyl group, in which R¹ isbenzyl or an amino protective group,

and/or a base of the formula I is converted into one of its salts bytreatment with an acid.

The compounds of the formula I′ and also the starting substances fortheir preparation are otherwise prepared by methods known per se, suchas are described in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), namely under reactionconditions which are known and suitable for the reactions mentioned. Inthis case, use can also be made of variants which are known per se butnot mentioned here in greater detail.

If desired, the starting substances can also be formed in situ such thatthey are not isolated from the reaction mixture, but immediately reactedfurther to give the compounds of the formula I.

In the compounds of the formula II, the radical Q is preferably Cl orBr; however, it can also be I, OH or a reactive modified OH group suchas alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) orarylsulfonyloxy having 6-10 C atoms (preferably phenyl- orp-tolylsulfonyloxy, 1- or 2-naphthalenesulfonyloxy). In the compounds ofthe formula II, the radical R is preferably Br or 4-benzylpiperazinyl.The compounds of the formula II are known in some cases; the unknowncompounds can easily be prepared analogously to the known compounds.

The reaction of the compounds of the formula II with compounds of theformula III proceeds according to methods such as are known from theliterature for the alkylation of amines. The components can be fusedwith one another without a solvent being present, if appropriate in aclosed tube or in an autoclave. However, it is also possible to reactthe compounds in the presence of an inert solvent. Suitable inertsolvents are, for example, hydrocarbons such as hexane, petroleum ether,benzene, toluene or xylene; chlorinated hydrocarbons such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers suchas ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethylglycol), ethylene glycol dimethyl ether (diglyme); ketones such asacetone or butanone; amides such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitrites such as acetonitrile; sulfoxides suchas dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such asnitromethane or nitrobenzene; esters such as ethyl acetate, andoptionally also mixtures of the solvents mentioned with one another ormixtures with water.

The addition of an acid-binding agent, for example of an alkali metal oralkaline earth metal hydroxide, carbonate or bicarbonate or of anothersalt of a weak acid of the alkali metals or alkaline earth metals,preferably of potassium, sodium or calcium, or the addition of anorganic base such as triethylamine, dimethylamine, pyridine or quinolineor of an excess of the amine component can be favourable. Depending onthe conditions used, the reaction time can be between a few minutes and14 days, and the reaction temperature between 0 and 150°, normallybetween 20 and 130° C.

In the compounds of the formula V, the radical Q′ is preferably Cl orBr; however, it can also be I, OH or a reactive modified OH group suchas alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) orarylsulfonyloxy having 6-10 C atoms (preferably phenyl- orp-tolylsulfonyloxy, or 1- or 2-naphthalenesulphonyloxy).

In the compounds of the formula IV, the radical R is preferably Br or4-benzylpiperazinyl.

The reaction of the compounds of the formula IV with compounds of theformula V proceeds according to methods such as are known from theliterature for the alkylation of phenols.

The compounds of the formula VI are known in some cases; the unknowncompounds can easily be prepared analogously to the known compounds. Thecyclization is carried out according to generally known methods.

The removal of an amino protective group from a compound of the formulaI—depending on the protective group used—is carried out, for example,using strong acids, expediently using TFA (trifluoracetic acid) orperchloric acid, but also using other strong inorganic acids such ashydrochloric acid or sulfuric acid, strong organic carboxylic acids suchas trichloroacetic acid or sulfonic acids such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but not always necessary.

Suitable inert solvents are preferably organic solvents, for examplecarboxylic acids such as acetic acid, ethers such as tetrahydrofuran ordioxane, amides such as dimethylformamide, halogenated hydrocarbons suchas dichloromethane, in addition also alcohols such as methanol, ethanolor isopropanol, and water. In addition, mixtures of the abovementionedsolvents are possible. TFA is preferably used in an excess withoutaddition of a further solvent, perchloric acid in the form of a mixtureof acetic acid and 70% perchloric acid, in the ratio 9:1. The reaction,temperatures are expediently between approximately 0 and approximately50°; the reaction is preferably carried out between 15 and 30°.

The group BOC is preferably removed using TFA in dichloromethane orusing approximately 3 to 5 N hydrochloric acid in dioxane at 15-30°.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) canbe removed, for example, by treating with hydrogen in the presence of acatalyst (e.g. of a noble metal catalyst such as palladium, expedientlyon a support such as carbon). Suitable solvents here are those indicatedabove, in particular, for example, alcohols such as methanol or ethanolor amides such as DMF. The hydrogenolysis is generally carried out attemperatures between approximately 0 and 100° and pressures betweenapproximately 1 and 200 bar, preferably at 20-30° and 1-10 bar.

Compounds of the formula I in which R′ isN,N-di(tert-butyloxycarbonyl)aminocarbonyl are preferably obtained byreaction of the unprotected aminocarbonyl compound, in which

R is 4-R¹-piperazinyl or L,

L [lacuna] the meaning indicated in claim 1 and

R¹ is benzyl or another amino protective group, with (BOC)₂O in an inertsolvent, such as, for example, THF or dioxane with addition of a base,such as, for example, diethylamine and preferably of a catalytic amountof dimethylaminopyridine.

A base of the formula I can be converted into the associated acidaddition salt using an acid, for example by reaction of equivalentamounts of the base and of the acid in an inert solvent such as ethanoland subsequent evaporation. Suitable acids for this reaction are inparticular those which give physiologically acceptable salts. Thus,inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as ortho-phosphoric acid, sulfamic acid, furthermore organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,e.g. formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methane- or ethanesulfonic acid, ethanedisulfonic acid,2-hydroxy-ethanesulfonic acid, benzenesulfonic acid, p-toluene-sulfonicacid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid.Salts with physiologically unacceptable acids, e.g. picrates, can beused for the isolation and/or purification of the compounds of theformula I.

On the other hand, compounds of the formula I can be converted usingbases (e.g. sodium or potassium hydroxide or carbonate) into thecorresponding metal, in particular alkali metal or alkaline earth metalsalts, or into the corresponding ammonium salts.

The invention furthermore relates to the use of the compounds of theformula I as intermediates for the synthesis of medicaments.Corresponding medicaments-are described, for example, in DE 4333254.

The invention relates in particular to the use of the compounds of theformula I as intermediates for the synthesis of medicaments whichexhibit actions on the central nervous system.1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazineand its salts are very particularly preferably to be mentioned here.

The invention accordingly relates in particular to the use of thecompounds of the formula I according to claim 1

in which

R is Cl, Br, I or 4-R¹-piperazinyl,

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-yl carbonyl,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

R¹ is benzyl or another amino protective group,

R⁴ is H, benzyl or another amino protective group,

R², R³ in each case independently of one another are H or alkyl having1-6 C atoms,

 in the synthesis of

1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazineand its salts, characterized in that

3-R-6-hydroxybenzaldehyde,

 in which R is Cl, Br or I,

is reacted with a compound of the formula VI

X—CH₂—CO—Q  VI

in which X is Cl, Br, I or a free or functionally modified OH group,

Q is OH or OR″ and

R″ is alkyl having 1-6 C atoms,

 to give a compound of the formula VII

 in which

R is Cl, Br or I,

and Q has the meanings indicated,

 in that, in the compound thus obtained, Q is converted into Cl, Br, Ior a functionally modified OH group,

in that the compound thus obtained is reacted with a compound of theformula III

R′—H  III

 in which

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-ylcarbonyl,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

and R², R₃ and R⁴ have the meanings indicated,

 to give a compound of the formula I

 in which

R is Cl, Br or I,

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-ylcarbonyl,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

R⁴ is H, benzyl or another amino protective group,

R², R³ in each case independently of one another are H or alkyl having1-6 C atoms,

 in that, in the compound of the formula I thus obtained, the radical Ris converted into another radical R,

 by reacting under transition metal catalysis with a compound of theformula VIII

4-R¹-piperazine  VIII

 in which

R¹ is benzyl or another amino protective group,

 to give a compound of the formula I

 in which

R is 4-R¹-piperazinyl,

R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-ylcarbonyl,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,

R¹ is benzyl or another amino protective group,

R⁴ is H, benzyl or another amino protective group,

R², R³ in each case independently of one another are H or alkyl having1-6 C atoms,

 in that the compound thus obtained of the formula I

i) is first converted by basic hydrolysis into a compound of the formulaIX and/or its acid addition salt

 in which

R is 4-R¹-piperazinyl and

R¹ is benzyl or another amino protective group,

 and then converted using ammonia into a compound of the formula X

 in which

R is 4-R¹-piperazinyl and

R¹ is benzyl or another amino protective group, or

ii) converted directly using ammonia into a compound of the formula X

 in which

R is 4-R¹-piperazinyl and

R¹ is benzyl or another amino protective group,

 in that the compound of the formula X thus obtained is converted into5-(1-piperazinyl)benzofuran-2-carboxamide or an acid addition salt byremoval of the amino protective group R¹, and

in that 5-(1-piperazinyl)benzofuran-2-carboxamide is reacted with3-(4-chlorobutyl)-5-cyanoindole to give1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazineand

optionally converted into its acid addition salt.

3-(4-Chlorobutyl)-5-cyanoindole is disclosed in DE 4101686;1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazineis disclosed in DE 4333254.

Above and below, all temperatures are indicated in ° C. In the followingexamples “customary working up” means: water is added, if necessary, thesolution is adjusted, if necessary, to a pH between 2 and 10 dependingon the constitution of the final product, and extracted with ethylacetate or dichloromethane, the organic phase is separated off, driedover sodium sulfate, evaporated and purified by chromatography on silicagel and/or by crystallization. R_(f) values on silica gel.

EXAMPLE 1 (2,5-Dimethylpyrrol-1-yl)-5-bromobenzofuran-2-yl-methanone

0.3 g of sodium hydride (60% suspension in paraffin oil) is introducedinto 10 ml of THF and 0.5 mL [sic] of 2,5-dimethylpyrrole in 10 ml ofTHF is added dropwise (5 minutes). After stirring at 50° C. for 1 hour,a reddish suspension is present. 1.3 g of 5-bromobenzofuran-2-carbonylchloride in 10 ml of THF is [sic] added dropwise at 25° C. (5 minutes)and the mixture is subsequently stirred for 2 hours. The addition of 100ml of completely deionized water and 100 ml of ethyl acetate follows.The separated organic phase was additionally washed 2× with 100 ml ofwater and concentrated in vacuo. After chromatography on silica gel(eluent heptane/ethyl acetate 4:1), the residual oil gives 700 mg ofyellow crystals (yield 44%), m.p. 115-116°.

EXAMPLE 2 5-Bromobenzofuran-2-carboxylic Acid Diethylamide

1.3 g. of 5-bromobenzofuran-2-carbonyl chloride, 1 mL [sic] ofethyldiisopropylamine and 30 mL [sic] of toluene are mixed and 0.62 mlof diethylamine is added to the brown-coloured solution with stirring. Aprecipitate is formed with a slightly exothermic reaction. After 5minutes, the mixture was treated with 30 ml of completely deionizedwater and the phases were separated. The organic phase was washed with1.) 20 ml of iN HCl 2.) 20 ml of iN NaOH 3.) 20 ml of water and thenwith 20 ml of saturated NaCl solution and then freed of solventcomponents in vacuo. After chromatography on silica gel the residual,yellowish oil forms in the eluent MtB ether/heptane 2:1 [sic]. Finalweight: 1.3 g of colourless crystals [sic] (yield: 88%), m.p. 79-81°.

EXAMPLE 3 Di-tert-Butyl N-(5-Bromobenzofuran-2-carbonyl)imidodicarbonate

12 g of 5-bromobenzofuran-2-carboxamide, 23.5 ml of BOC₂O, 600 mg ofDMAP and 8 ml of triethylamine are introduced into 100 ml of THF at 20°C. A clear, orange solution is formed in 3 h in an endothermic reaction.It is warmed to 25° C. and treated with 100 ml of water and 100 ml ofethyl acetate. The organic phase is separated off, and washed twice with100 ml of water and 100 ml of saturated sodium chloride solution. Theorganic phase is concentrated and forms a mixture of oil and crystals(22 g/yield 40%). After crystallization of the crude product from 160 mlof ethanol, 9.0 g of yellow crystals are obtained, m.p. 138-139°.

EXAMPLE 4 5-Bromobenzofuran-2-carboxylic Acid Dibenzylamide

A solution of 50 ml of toluene and 7.9 g of dibenzylamine are addeddropwise with stirring at 50-60° C. in the course of 10 min. to 5.2 g of5-bromobenzofuran-2-carbonyl chloride in 100 ml of toluene. A colourlesssolid is obtained. After dropwise addition is complete, the mixture isadditionally stirred at 100-110° C. for a further 3 hours. After coolingto 10° C., the solid product (dibenzylammonium chloride) is filtered offwith suction. The filtrate is then treated with a mixture of 150 ml ofwater and 10 g of sodium carbonate and thoroughly shaken. The organicphase is separated off, washed again with 100 ml of water, dried usingsodium sulfate and filtered. The, filtrate is concentrated on aRotavapor in vacuo to a residue (residue: 9.5 g). Afterrecrystallization from 100 ml of methanol, 6.5 g of product (yield 77%)remain after isolation.

m.p. 114-115°.

EXAMPLE 5 5-(4-Benzylpiperazin-1-yl)bromobenzofuran-2-carboxylic AcidDibenzylamide

0.06 mg of Pd2DBA3 [sic] and 0.007 g of2-dicyclohexylphosphino-2′-dimethylaminobiphenyl in 40 ml of toluene wasstirred under nitrogen at 25° C. for 20 min. 1.58 g of5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid dibenzylamide, 0.98 g of1-benzylpiperazine and 1.43 g of sodium tert-butylate are then added andthe mixture is stirred at 120° C. for 2 hours. The cooled reactionmixture is stirred into a mixture of 150 ml of water and 5 ml of 37%hydrochloric acid with stirring [sic]. The reaction mixture isneutralized with 1.5 g of sodium carbonate and the phase is [sic]extracted 3 times with 100 ml of ethyl acetate. The combined organicphases are dried with 5 g of sodium sulfate and the filtrate isconcentrated in vacuo to give a resinous residue (1.8 g of crudeproduct). The crude product is dissolved in 100 ml of ethyl acetate,clarified with activated carbon and filtered. By addition of 25 ml of2-molar ethanolic hydrochloric acid, the piperazine product isprecipitated as the hydrochloride, filtered, and the crystals are washedwith 10 ml of ethyl acetate and dried in vacuo at 40° C. Final weight:1.5 g/yield 53%, m.p. 196-198°.

EXAMPLE 6 cis/trans-1,2-Di(5-Bromobenzofuran)-2-ylethene

A) Preparation of the Diether

The compound is obtained by reaction of 5-bromosalicylaldehyde withCl—CH₂—CH═CH—CH₂—Cl.

B) The Dibenzofuran Derivative is Obtained by Cyclization.

EXAMPLE 7 2,2′-Ethyndiyl-bis-5-bromobenzofuran

A) Preparation of the diether

Reaction of 5-bromosalicylaldehyde with Cl—CH₂—CC—CH₂—Cl.

B) Cyclization of the Diether.

What is claimed is:
 1. A benzofuran derivative of formula I

wherein R is 1-piperazinyl, 4-R¹-piperazinyl or L, R′ is2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-ylcarbonyl,N,N-di(tert-butyloxycarbonyl)aminocarbonyl, —CH═C(R⁵R⁶),benzofuran-2-yl-C≡C—, —C(Hal)₃, —CO—C(Hal)₃,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl, L is Cl, Br, I or an OH ora reactive functionally modified OH group, R¹, R⁴ in each caseindependently of one another are H, benzyl or another amino protectivegroup, R², R³ in each independently of one another are H or alkyl having1-6 C atoms, R⁵, R⁶ in each case independently of one another are alkylhaving 1-6 C atoms, and Hal is F, Cl, Br or I, or a salt thereof.
 2. Acompound selected from the group consisting of a)(5-Bromobenzofuran-2-yl)-(2,5-dimethylpyrrol-yl)methanone b)(4-Benzylpiperazin-1-yl)-[5-(4-benzylpiperazin-1-yl)benzofuran-2-yl]methanone;c)[5-(4-Benzylpiperazin-1-yl)benzofuran-2-yl]-(1,4-dihydrobenzo[d][1,2]oxazin-3-ylmethanone;d)[5-(4-Benzylpiperazin-1-yl)benzofuran-2-yl]-(3,4-dihydro-1H-phthalazin-2-yl)methanone;or e) 5-Bromo-2-(2-methylpropenyl)benzofuran; or a salt thereof.
 3. Aprocess for preparing a benzofuran derivative of formula I according toclaim 1, wherein R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, andR′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl, 4-R⁴-piperazin-1-ylcarbonyl,1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonyl or3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl, said process comprisingreacting a compound of formula II

wherein R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, and Q is Cl,Br, I or an OH or a reactive functionally modified OH group,  wherein R¹has the meaning indicated in claim 1, with a compound of formula IIIR′—H  III wherein R′ is 2-R²-5-R³-pyrrol-1-yl, 4-R⁴-piperazin-1-yl,1,4-dihydrobenzo[d][1,2]oxazin-3-yl or3,4-dihydrobenzo-1H-phthalazin-2-yl, wherein R², R³ and R⁴ have themeanings indicated in claim
 1. 4. A method for preparing1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazinecomprising reacting 3-R-6-hydroxybenzaldehyde, wherein R is Cl, Br or I,with a compound of formula VI X—CH₂—CO—Q  VI wherein X is Cl, Br, I oran OH or a functionally modified OH group, Q is OH or OR″ and R″ isalkyl having 1-6 C atoms, to provide a compound of formula VII

wherein R is Cl, Br or I,and Q has the meanings indicated above,  thenconverting Q into Cl, Br, I or a functionally modified OH group, thenreacting the resultant compound with a compound of formula III R′—H  IIIwherein R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl,4-R⁴-piperazin-1-ylcarbonyl, 1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonylor 3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl,  wherein R⁴ is H, benzylor another amino protective group, R^(2, R) ³ in each case independentlyof one another are H or alkyl having 1-6 C atoms, to provide a compoundof the formula I

wherein R is Cl, Br or I, R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl,4-R⁴-piperazin-1-ylcarbonyl, 1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonylor 3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl, R⁴ is H, benzyl oranother amino protective group, R², R³ in each case independently of oneanother are H or alkyl having 1-6 C atoms,  then converting R of theresultant compound of formula I into another radical R, by reacting saidcompound of formula I under transition metal catalysis with a compoundof formula VIII 4-R¹-piperazine  VIII  wherein R¹ is benzyl or an aminoprotective group, to provide a compound of the formula I  wherein R is4-R¹-piperazinyl, R′ is 2-R²-5-R³-pyrrol-1-ylcarbonyl,4-R⁴-piperazin-1-ylcarbonyl, 1,4-dihydrobenzo[d][1,2]oxazin-3-ylcarbonylor 3,4-dihydrobenzo-1H-phthalazin-2-ylcarbonyl, R¹ is benzyl or an aminoprotective group, R⁴ is H, benzyl or another amino protective group, R²,R³ in each case independently of one another are H or alkyl having 1-6 Catoms, followed by either i) converting the resultant compound offormula I by basic hydrolysis into a compound of formula IX and/or itsacid addition salt

 wherein R is 4-R¹-piperazinyl and R¹ is benzyl or another aminoprotective group, and then converting the resultant compound of formulaIX by using ammonia into a compound of formula X

 wherein R is 4-R¹-piperazinyl and R¹ is benzyl or another aminoprotective group, or ii) converting the resultant compound of formula Iby using ammonia into a compound of formula X

 wherein R is 4-R¹-piperazinyl and R¹ is benzyl or another aminoprotective group, then converting the resultant compound of formula Xinto 5-(1-piperazinyl)benzofuran-2-carboxamide or an acid addition saltof it by removing the protective group R¹ and reacting the5-(1-piperazinyl)benzofuran-2-carboxamide with3-(4-chlorobutyl)-5-cyanoindole to provide1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazineand optionally then converting it into its acid addition salt.
 5. Aprocess for preparing a benzofuran derivative of formula I according toclaim 1 wherein R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, andR′ is —CH═C(R⁵R⁶), benzofuran-2-yl-C≡C—, —C(Hal)₃ or —CO—C(Hal)₃,wherein R¹, R⁵ and R⁶ have the meanings indicated in claim 1, saidprocess comprising reacting a compound of formula IV

wherein R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, with acompound of formula V Q′—CH₂—CO—R′  V wherein R′ is —CH═C(R¹R⁶),benzofuran-2-yl-C≡C—, —C(Hal)₃ or —CO—C(Hal)₃, and Q′ is Cl, Br, I or anOH or a reactive functionally modified OH group, wherein R⁵ and R⁶ havethe meanings indicated in claim
 1. 6. A process for preparing abenzofuran derivative of formula I according to claim 1 wherein R is Cl,Br, I, 1-piperazinyl or 4-R¹-piperazinyl, and R′ is —CH═C(R⁵R⁶),benzofuran-2-yl-C≡C—, —C(Hal)₃ or —CO—C(Hal)₃, wherein R¹, R⁵ and R⁶have the meanings indicated in claim 1, said process comprisingcyclizing a compound of formula Va

wherein R is Cl, Br, I, 1-piperazinyl or 4-R¹-piperazinyl, and R′ is—CH═C(R⁵R⁶), benzofuran-2-yl-C≡C—, —C(Hal)₃ or —CO—C(Hal)₃.
 7. A processfor preparing a benzofuran derivative of formula I according to claim 1wherein R is a 1-piperazinyl radical, said process comprising convertingby introducing an amino protective group into another compound offormula I wherein R is a 4-R¹-piperazinyl radical, and wherein R¹ is anamino protective group.
 8. A process for preparing a benzofuranderivative of formula I according to claim 1 wherein R is a4-R¹-piperazinyl group, and R¹ is benzyl or another amino protectivegroup, said process comprising converting by removing the benzyl oranother amino protective group into a compound of formula I wherein R¹is 1-piperazinyl.
 9. A process for preparing a benzofuran derivative offormula I according to claim 1 wherein in a compound of formula I aradical R is converted into another radical R, said process comprisingreplacing a Br atom by OH, esterifying an OH group or replacing a Bratom by a 4-R¹-piperazinyl group, wherein R¹ is benzyl or an aminoprotective group.
 10. A process for preparing a salt of a benzofuranderivative of formula I according to claim 1 comprising converting abase of a compound of formula I into one of its salts by treatment withan acid.
 11. A benzofuran derivative of formula I according to claim 1wherein the reactive functionally modified OH group is selected from thegroup consisting of an activated ester, an imidazolide, analkylsulfonyloxy having 1 to 6 Carbon atoms, and an arysulfonyloxyhaving 6 to 10 Carbon atoms.
 12. A benzofuran derivative of formula Iaccording to claim 1 wherein the reactive functionally modified OH groupis selected from the group consisting of methylsulfonyloxy,phenyl-tolylsulfonyloxy and p-tolylsulfonyloxy.
 13. A process accordingto claim 3, wherein Q is Cl or Br, and R is Br or 4-benzylpiperazinyl.14. A process according to claim 5, wherein Q′ is Cl or Br, and R is Bror 4-benzylpiperazinyl.
 15. A method of preparing a pharmaceuticalcompound wherein a compound of formula I according to claim 1 is anintermediate compound in the synthesis of the pharmaceutical compound.16. A method of treating a condition of the central nervous systemcomprising administering an effective amount of a compound prepared by amethod according to claim 15 to a patient.